Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions

Definitions

• the present invention relates to a method for preparing an aqueous solution or dispersion comprising peracetic acid, the aqueous solution or dispersion prepared according to the method and its use in an antimicrobial intervention to protect animals.
• Antibiotic resistance is the major global problem facing healthcare. Nowhere is this more important than in animal health and husbandry, where misuse and overuse of antibiotics not only as anti-infectives, but also as growth promoters has created widespread reservoirs of resistant infection capable in some cases of transferring to the human population.
• the primary objective is reduction or elimination of pathogens in the gastro intestinal tract, or otherwise modifying the gut microbiome to enhance the health of the animal and as collateral benefit deliver improvements in population survival rates, body weight gain, and feed intake efficiency.
• the organoleptic properties and safety of the reared food product must not be compromised.
• the economic considerations of treating billions of feed animals, for example just poultry are of a different type and magnitude.
• the treatment can only cost pence per bird life cycle as compared to maybe thousands of pounds per patient in human medicine. This is especially important in applying the treatment to animals in low and middle income countries and across a range of agricultural enterprises from the small holding to the largest industrialised units.
• Highly oxidative molecules exert a powerful biocidal effect and microorganisms by inflicting massive and widely disseminated damage to the bacterial cell owing to the high energy transfer capability of these molecules. Therefore, resistance to these chemicals is rare. Examples of such molecules would be ozone, hypochlorous acid, sodium hypochlorite or hypobromite, chlorine dioxide, peracids such as peracetic acid and hydrogen peroxide.
• Hydrogen peroxide is widely used in endodontics, in the treatment of periodontitis and as an antiseptic for wounds and mucous membranes.
• Dilute solutions of hypochlorous acid have been advocated for topical disinfection and peracetic acid has been widely used in dairy hygiene as a pre- and post-milking teat disinfectant.
• the object of the present invention was to overcome the problems of the prior art cited described above.
• the object of the present invention was to provide an aqueous solution or dispersion suitable as animal drink or animal feed and a method for its preparation, which achieves a suitable peracetic acid (PAA) concentration in the aqueous solution or dispersion, e.g. 30-70 ppm, preferably 40-60 ppm, in a relatively constant manner over the time.
• PAA peracetic acid
• the suitable PAA concentration should be reached after a relatively short time.
• the inventors have now surprisingly found that the object can be achieved by the following method.
• Administering a two component system to an aqueous solution or dispersion wherein the first component is a mixture of an acetyl donor and a peroxygen donor, preferably in combination with a chelating agent.
• the second component is an organic acid to buffer the pH value (pH modifying agent) which is only mixed with the first mixture after a defined time period selected to optimise the release of peracid in the water supply.
• pH value pH modifying agent
• the levels and precise ratios of the chemicals in both components may be adjusted to provide optimum dosing taking account of the metal ion content and pH of the particular farm water supply.
• the present invention is directed to a method for preparing an aqueous solution or dispersion comprising peracetic acid, comprising the steps of: adding a peroxygen donor and an acetyl donor to an aqueous solution or dispersion to prepare an aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor, which generate peracetic acid and hydrogen peroxide over the course of time, and adding an organic acid to the aqueous solution or dispersion 10 min or later, such as 15 min or later after the preparation of the aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor to buffer the pH of the aqueous solution or dispersion.
• first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another.
• a first object or step could be termed a second object or step, and, similarly, a second object or step could be termed a first object or step.
• the first object or step, and the second object or step are both objects or steps, respectively, but they are not to be considered the same object or step.
• ppm refers to ppm by weight unless otherwise stated.
• An aqueous solution or dispersion as used herein also encompasses an aqueous emulsion.
• the first step comprises: adding a peroxygen donor and an acetyl donor to an aqueous solution or dispersion to prepare an aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor, which generate peracetic acid and hydrogen peroxide in the course of time.
• the rate of the reaction is not very fast so that the generation of peracetic acid and hydrogen peroxide proceeds over a certain time span.
• the aqueous solution or dispersion to which the peroxygen donor and the acetyl donor is added is preferably water, more preferably drinking water such as tap water, council water, domestic water.
• drinking water here refers to drinking water suitable for animals, in particular for poultry, such as chicken, ducks and/or turkeys, in particular chicken.
• the aqueous solution or dispersion may further comprise one or more additives such as dyes, flavors, taste masking agents, emulsifiers, enhancers, chelating agents, essential oils, herbal extracts, organic fatty acids, nutritional supplements, items of traditional Chinese medicine and/or preservatives.
• the one or more additives can be added to the aqueous solution or dispersion before, during and/or after, preferably before, the addition of the peroxygen donor and an acetyl donor.
• a preferred additive is a chelating agent, which is discussed below in more detail.
• the aqueous solution or dispersion preferably water, in particular drinking water, to which the peroxygen donor and the acetyl donor is added has preferably a pH value in the range of 5.0 to 9.5, preferably 6.0 to 9.0 or 6.5 to 9.0, more preferably 7.0 to 8.5.
• the peroxygen donor is a compound that is capable of forming hydrogen peroxide in the aqueous solution or dispersion.
• the acetyl donor is a compound that is capable to react with the hydrogen peroxide generated to produce a mixture of peracetic acid and hydrogen peroxide.
• the peroxygen donor and the acetyl donor can be added independently from each other as a fluid, e.g. as a solution in a solvent such as water, or more preferably as a solid such as a powder.
• the peroxygen donor and the acetyl donor can be added to the aqueous solution or dispersion separately or as a mixture. It is preferred that the peroxygen donor and the acetyl donor are added simultaneously or nearly simultaneously, e.g. within less than 2 min, more preferably within 1 min, wherein a simultaneous addition is preferred.
• the peroxygen donor and the acetyl donor are added as a solid mixture of the peroxygen donor and the acetyl donor to the aqueous solution or dispersion.
• the aqueous solution or dispersion preferably water, in particular drinking water, comprising the peroxygen donor and the acetyl donor further comprise a chelating agent, i.e. a chelating agent is also added to the aqueous solution or dispersion.
• the chelating agent can be added before, during or after the addition of the acetyl donor and the acetyl donor, preferably before or during the addition of the acetyl donor and the acetyl donor.
• the chelating agent can be added in solid form such as a powder or as a fluid, such as a solution of the chelating agent in a solvent such as water, wherein it is preferably added in solid form.
• a chelating agent is also added to the aqueous solution or dispersion, it is a preferred embodiment that the peroxygen donor, the acetyl donor and the chelating agent are added as a solid mixture of the three components to the aqueous solution or dispersion.
• metal ions which may be present in an aqueous solution or dispersion, such as water, in particular drinking water, can interfere with the reaction of the peroxygen donor and the acetyl donor to produce a mixture of peracetic acid and hydrogen peroxide.
• Chelating agents can mask metal ions present in the aqueous solution or dispersion such as e.g. sodium, potassium, magnesium, calcium and/or iron ions.
• the addition of a chelating agent is beneficial if metal ions are present in the aqueous solution or dispersion, which significantly affects the reaction the peroxygen donor and the acetyl donor.
• chelating agent serves to mask interfering metal ions in the aqueous solution or dispersion, which improves the desired reaction between the peroxygen donor and the acetyl donor.
• chelating agent usually have acidic characteristics so that the pH of the aqueous solution or dispersion can be increased, if the amount of the chelating agent added is too high.
• an increased pH value interferes with the reaction of the peroxygen donor and the acetyl donor to produce a mixture of peracetic acid and hydrogen peroxide which is not desired. Therefore, an amount of chelating agent added to the aqueous solution or dispersion should be rather low.
• the amount of the chelating agent may be, for instance, not more than 0,050 wt.%, more preferably 0,002 to 0,040 wt.%, more preferably 0,005 to 0,020 wt.%, based on the weight of the aqueous solution or dispersion.
• any compound known to be suitable as peroxygen donor or a mixture thereof can be used.
• the peroxygen donor can be selected e.g. from sodium perborate, ammonium perborate, sodium percarbonate, potassium percarbonate, ammonium percarbonate, sodium perphosphate, ammonium persulphate, urea peroxide, peresters, superoxides, dioxygenyl, ozones, hydrogen peroxide, lithium peroxide, barium peroxide, di-tert-butyl peroxide, ammonium peroxydisulphate and potassium peroxymonosulphate or any mixture thereof, wherein sodium percarbonate, potassium percarbonate, ammonium percarbonate, sodium perborate, ammonium perborate, ammonium persulphate, urea peroxide or any mixture thereof are particularly preferred.
• the most preferable peroxygen donor is sodium percarbonate (SP).
• the acetyl donor can be selected from tetraacetylethylenediamine (TAED), methyl cellulose encapsulated TAED, acetyl salicylic acid, diacetyl dioxohexahydratriazine (DADHT), tetraacetyl glycoluril, acetyl urea, di-acetyl urea, tri-acetyl urea, pentaacetyl glucose (PAG), tetraacetyl glycoluril (TAGU), acetyl phosphate, acetyl imidazole, acetyl CoA, acetic anhydride, compounds containing a hemiacetal group, acetic acid, diacetylmorphine, pyruvate, acetyl chloride, acetyl
• TAED tetraacetylethylenediamine
• any compound known to be suitable for masking (chelating) metal ions can be used.
• the chelating agent are ethylenediaminetetraacetic acid (EDTA) and 1-hydroxy ethylidene-1,1- diphosphonic acid (HEDP).
• the peroxygen donor and the acetyl donor are added to the aqueous solution or dispersion in such amounts that the weight ratio of the peroxygen donor to the acetyl donor is from 4: 1 to 1:0.5, preferably 3: 1 to 1: 1, more preferably 2: 1 to 1: 1.
• the peroxygen donor is added, based on the weight of the aqueous solution or dispersion, in an amount in the range of 0.0135 to 0.0315 wt.%, 0.0155 to 0.0300 wt.%, more preferably 0.0200 to 0.0250 wt.%.
• the acetyl donor is added, based on the weight of the aqueous solution or dispersion, in an amount in the range of 0.0090 to 0.0210 wt.%, preferably 0.0100 to 0.0200 wt.%, more preferably 0.0135 to 0.0165 wt.%.
• the aqueous solution or dispersion is stirred at least until the addition of the organic acid.
• an organic acid is added to the aqueous solution or dispersion 10 min or later, such as 15 min or later after the preparation of the aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor to buffer the pH of the aqueous solution or dispersion. That is, the starting point is when both the peroxygen donor and the acetyl donor are included in the aqueous solution or dispersion.
• the addition of the organic acid takes place at the earliest 10 min after this starting point, such as at the earliest 15 min after this starting point.
• the inventors have found that the reaction of the peroxygen donor and the acetyl donor is significantly affected, if the organic acid is added to the aqueous solution or dispersion together with the peroxygen donor and the acetyl donor. Unexpectedly, this inhibiting effect of the organic acid could be overcome or alleviated when it is added to the aqueous solution or dispersion only after 10 min or more, such as after 15 min or more after the preparation of the aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor.
• the organic acid is added 10 min to 4 h, such as 10 min to 3 h, such as 10 min to 2 h, after the preparation of the aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor.
• the organic acid is added 15 min to 4 h, such as 15 min to 3 h, such as 15 min to 2 h, after the preparation of the aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor.
• the organic acid is added 10 to 90 min, such as 15 to 90 min, more preferably 10 to 60 min, such as 15 to 60 min, after the preparation of the aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor.
• the organic acid may one organic acid or a combination of two or more organic acids. Any suitable organic acid can be used to buffer the aqueous solution or dispersion.
• the organic acid may be an organic compound having one or more carboxylic groups. Suitable examples for the organic acid are citric acid, organic fatty acids, sorbic acid, tartaric acid, glutaric acid, glycolic acid or any mixtures thereof, with citric acid being preferred.
• the organic acid preferably citric acid
• the organic acid is preferably added in an amount of 0.0020 to 0.0300 wt.%, preferably 0.0050 to 0.0250 wt.%, more preferably 0.0060 to 0.0200 wt.%, based on the weight of the aqueous solution or dispersion. It should be noted, however, that the amount of organic acid should be adjusted such that the pH of the aqueous solutions or dispersion is adjusted to a value as indicated below. The amount of the organic acid needed can therefore vary from these amounts.
• the organic acid is added in such a proportion that the pH of the aqueous solution or dispersion is adjusted to a pH of 6.0 to 9.0, preferably 6.5 to 8.2, more preferably 6.5 to 7.0.
• the pH values refers to the values determined after the addition of the citric acid.
• the aqueous solution of the invention preferably includes, based on the weight of the aqueous solution or dispersion,
• the peroxygen donor such as sodium percarbonate (SP)
• acetyl donor such as tetraacetylethylenediamine (TAED)
• TAED tetraacetylethylenediamine
• a chelating agent preferably not more than 0,050 wt.%, more preferably 0,002 to 0,040 wt.%, more preferably 0,005 to 0,020 wt.%, of a chelating agent, such as EDTA or HEDP.
• the balance is typically water or water containing further additives.
• the aqueous solution or dispersion achieves a suitable peracetic acid (PAA) concentration in the aqueous solution or dispersion, e.g. in the range of 30- 70 ppm, preferably 40-60 ppm.
• PAA peracetic acid
• the desired PAA concentration can be achieved relatively shortly after the preparation of the aqueous solution or dispersion of the invention, i.e. after addition of the organic acid.
• the aqueous solution or dispersion is preferably an animal feed or animal drink, in particularly an animal drink. This refers to both the aqueous solution or dispersion to which the peroxygen donor and an acetyl donor are added and to the aqueous solution or dispersion comprising peracetic acid, i.e. the aqueous solution or dispersion comprising peracetic acid, obtained by the inventive method.
• Animal drink shall be understood as any liquid given to domestic animals, especially livestock, in the course of animal husbandry.
• Animal drink as understood herein is usually based on water or consist of water as the sole solvent or dispersant for any actives, precursors, or additives.
• the present invention is also directed to the aqueous solution or dispersion comprising peracetic acid, which is obtainable by the inventive method as described above.
• inventive method as described above.
• all general and preferred feature and embodiments described above for the inventive method also apply to the inventive aqueous solution or dispersion comprising peracetic acid.
• the inventive aqueous solution or dispersion comprising peracetic acid is preferably an animal feed or animal drink, in particular an animal drink.
• the animal drink or animal food is preferably for poultry, such as chicken, ducks and/or turkeys, in particular chicken.
• the present invention is also directed to the aqueous solution or dispersion comprising peracetic acid for use in an antimicrobial intervention to protect animals.
• the animal is preferably poultry, such as chicken, ducks and/or turkeys, in particular chicken.
• the aqueous solution or dispersion for use in an antimicrobial intervention to protect animals according to the invention is preferably for use in the treatment or prevention of an infection of an animal, wherein the animal is preferably poultry, such as chicken, ducks and/or turkeys, in particular chicken.
• Infections may comprise bacterial infections such as by (without limitation) microorganisms causing Salmonellosis, Shigellosis, Coccidiosis, E-coli infections, botulism, fowl cholera, Marek's disease, infectious bronchitis, mycoplasmosis, and infectious coryza, but not limited to these.
• Infections may also comprise infections by antibiotic resistant bacteria and MDROs (multi-drug resistant organisms).
• Infections may also comprise viral, like fowl pox, Newcastle disease and avian flu, and/or fungicidal infections.
• aqueous solution or dispersion for use in an antimicrobial intervention to protect animals according to the invention is also suitable for use to create a beneficial reduction in bacterial numbers or a beneficial alteration in bacterial spectrum in the gut microbiome in animals, wherein the animal is preferably poultry such as chicken, ducks and/or turkeys, in particular chicken.
• the present invention is also directed to a kit of parts, comprising a first package and a second package, wherein the first package contains a solid mixture of a peroxygen donor, an acetyl donor and optionally a chelating agent, and the second package contains an organic acid, preferably a solid organic acid.
• the weight ratio of the peroxygen donor to the acetyl donor in the first package is from 4: 1 to 1:0.5, preferably 3: 1 to 1: 1, more preferably 2: 1 to 1: 1.
• the weight ratio of the combined weight of the peroxygen donor and the acetyl donor in the first package to the weight of the organic acid in the second package is from 10: 1 to 1: 1, preferably 8: 1 to 2: 1, more preferably 6: 1 to 4: 1.
• the first and second package can be any suitable package to store solid materials.
• the first and second package may be a container or a pouch.
• the details and preferred embodiments described above for the inventive method equally apply with respect to the inventive kit of part, in particular with respect to the peroxygen donor, the acetyl donor, the chelating agent, the organic acid and possible further additives and the proportions thereof.
• the total weight of the peroxygen donor, the acetyl donor and optionally the chelating agent preferably amounts to 80 to 100% by weight, preferably 90 to 100% by weight of the content of the first package.
• the total weight of the organic acid, preferably solid organic acid, preferably amounts to 80 to 100% by weight, preferably 90 to 100% by weight of the content of the second package.
• kit of parts of the invention can be suitably used to prepare the aqueous solution or dispersion of the invention, wherein the proportions of the ingredients in the first and second package are typically adjusted in a suitable manner so that the aqueous solution or dispersion of the invention can be simply prepared by adding a predetermined amount of the content of the first package to an aqueous solution or dispersion, preferably mixing the mixture obtained, storing the mixture for at least 10 min, such as for at least 15 min, and than adding an amount of the content of the second package to complete the preparation of the inventive aqueous solution or dispersion.
• an inorganic acid instead of an organic acid is used to prepare the aqueous solution or dispersion.
• the invention is directed to a method for preparing an aqueous solution or dispersion comprising peracetic acid, comprising the steps of: adding a peroxygen donor and an acetyl donor to an aqueous solution or dispersion to prepare an aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor, which generate peracetic acid and hydrogen peroxide over the course of time, and adding an inorganic acid to the aqueous solution or dispersion 10 min or later, such as 15 min or later after the preparation of the aqueous solution or dispersion comprising the peroxygen donor and the acetyl donor to buffer the pH of the aqueous solution or dispersion.
• the invention is also directed to a kit of parts, comprising a first package and a second package, wherein the first package contains a solid mixture of a peroxygen donor, an acetyl donor and optionally a chelating agent, and the second package contains an inorganic acid, preferably a solid inorganic acid.
• the starting materials used are as follows:
• Peroxygen donor sodium percarbonate (SP)
• Acetyl donor tetraacetylethylenediamine (TAED)
• Organic acid citric acid and others
• a mixture of SP, TAED and EDTA - all in solid form - are added to the stirred aqueous solution.
• Citric acid is added separately as a solid to the aqueous solution at varying points of time with respect to the addition of the mixture of SP, TAED and EDTA (at the same time, after 5 min, 10 min, 15 min and 30 min, respectively). For each point of time, three trials were carried out.
• the pH value and the concentration of PAA in the aqueous solution was measured periodically. The PAA concentration was determined by means of a spectrophotometer.
• Time 0.00 hours represents the time just before the mixture of SP, TAED and EDTA is added.
• PAA In-water peracetic acid
• SP sodium percarbonate
• TAED tetraacetylethylenediamine
• a total of 96 Ross 308 male day-old chickens were used during the trial duration (randomised block design with 2 rooms, 12 pens per room, 4 birds per pen and 4 pens per level of inclusion), whilst PAA treatment was administered during the last week.
• Six different PAA levels of inclusion were tested through in-water daily administration of SP and TAED precursors.
• Possible PAA effect on body weight gain (BWG), FCR (feed conversion ratio), feed/water intake and BN (bacterial number) were assessed through fitting linear mixed model (i.e. treatment as fixed effect and hierarchy of room/pen/bird when possible as random effect). Longitudinal data were used when repeated measures were taken.
• Total bacterial number in DNA extracted from crop, jejunum and caecal content was calculated through qPCR targeting 16S rRNA gene (V3 region). Study design and protocol were approved by SRUC Animal Welfare and Review Body (POU AE 20-2019).
• control treatment at Oppm was associated with the lowest BWG and highest BN ( Figure 6).
• Figure 6 shows the observed effect of PAA on crop loglO BN. The latter was significantly correlated to BWG especially when PAA was administered at 40ppm. This could indicate a possible correlation between PAA and performance through interacting with upper-gut microbiota.
• An aqueous solution was prepared by adding the following ingredients in water
• the PAA concentration in the aqueous solution was determined within a span of 2 hours after addition of the ingredients.
• citric acid was replaced by the following acids: tartaric acid, sorbic acid, glutaric acid, glycolic acid, and a combination of citric and tartaric acid, respectively.
• Aqueous solutions used were prepared with a first powder consisting of a mixture of SP, TAED and EDTA and a second powder which is citric acid.
• the aqueous solutions obtained had the following composition:
• the aqueous solution is prepared and supplied as the animal drink for the chickens in the shed according to the following procedure:
• Step 1 add the first powder (SP, TAED and EDTA) to the predetermined volume of water.
• Step 3 add corresponding quantity of second powder (citric acid). • Step 4: mix for further 15 min
• Step 5 leave for 24 hours.
• Step 6 link the completed mix to the water line for the shed and dispense through filter and dosing equipment to deliver the desired concentration of PAA, 30-70 ppm, throughout the shed. Concentration checked at various points, nipple drinkers and pipe ends.
• the amount of citric acid was adjusted to obtain a pH between 6 and 9 in the aqueous solution.
• the time span of the study was from day 1 to day 39. Different amounts of aqueous solutions were prepared for each day of supply based on the amount of water consumed (as the chickens grow they require more water).
• aqueous solution of the invention was prepared essentially as in Example 4. Each aqueous solution was prepared the day before and fed through the Dosatron in the water lines at varying percentages (between 1-5%). Samples were taken from the lines and analysed for PAA content and it was determined that between 30-50ppm PAA was generated. Vitamins were fed for the first 5 days. PAA was fed from day 6 to day 41.
• Huwa-San TR-50 was discontinued from day 1 of the trial in shed 2 (Huwa-San TR-50 is a 50% hydrogen peroxide solution used to clean the water lines).

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2023
  • 2023-02-02 GB GB2512160.9A patent/GB2641856A/en active Pending
  • 2023-02-02 EP EP23704407.8A patent/EP4658237A1/de active Pending
  • 2023-02-02 WO PCT/GB2023/050233 patent/WO2024161097A1/en not_active Ceased

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